2. Academic Validation
  3. Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)pyridine derivatives as novel FLT3-ITD inhibitors

Design, synthesis, and biological evaluation of 4-(2-fluorophenoxy)pyridine derivatives as novel FLT3-ITD inhibitors

  • Eur J Med Chem. 2025 May 5:289:117492. doi: 10.1016/j.ejmech.2025.117492.
Shengfei Wu 1,  Pengjuan Zhao 1,  Youli Hou 1,  Lihong He 1,  Zhongyuan Wang 2,  Dan Yang 3,  Yue'e Chai 1,  Junji Liu 4,  Yulong Shen 5,  Aihong Li 1,  Xing Cui 1,  Dongsheng Zhao 1,  Bilan Luo 6,  Jianta Wang 1,  Lan Liu 7,  Weike Liao 8,  Yu Zhang 9
Affiliations

Affiliations

  • 1 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550004, China.
  • 2 Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, 550002, China.
  • 3 Clinical Medical Research Center, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Road, Yunyan Zone, Guiyang, 550004, China.
  • 4 Department of Respiratory Medicine, The Central Hospital of Shaoyang, Shaoyang, 422000, China.
  • 5 Department of Radiation Oncology, The Ninth Medical Center of Chinese PLA General Hospital, Beijing, 100101, China.
  • 6 Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
  • 7 Department of Respiratory Medicine, The Central Hospital of Shaoyang, Shaoyang, 422000, China. Electronic address: Liulan19841021@126.com.
  • 8 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550004, China. Electronic address: liaoweike2009@126.com.
  • 9 State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D, School of Pharmaceutical Sciences, Guizhou Medical University, Guiyang, 550004, China. Electronic address: zhangyugmc@126.com.
PMID: 40081102 DOI: 10.1016/j.ejmech.2025.117492
Abstract

FMS-like tyrosine kinase 3 (FLT3) is an ideal drug target for the treatment of acute myeloid leukemia (AML). Although several FLT3 inhibitors have been approved or evaluated in clinical trials, selectivity over c-Kit kinase and FLT3 WT remains a major challenge. Herein, we report a series of 4-(2-fluorophenoxy)pyridine derivatives with potent inhibitory activities against FLT3 internal tandem duplication (FLT3-ITD). The representative compound 13v inhibited FLT3-ITD kinase and isogenic BaF3-FLT3-ITD cells with nanomolar IC50 values and achieved selectivity over c-Kit (>53-fold) and FLT WT (19-fold) in transformed BaF3 cells. In addition, compound 13v displayed excellent selectivity against FLT3-ITD driven AML cells compared to Other leukemia cells, solid tumors, and normal peripheral blood mononuclear cells. Mechanistic studies revealed that 13v disrupted FLT3 signal transduction and induced G0/G1 cell cycle arrest and Apoptosis. Moreover, it also showed good developmental profiles in ADME assays. In in vivo studies, 13v demonstrated desirable pharmacokinetic (PK) profiles and sufficient tumor growth inhibition in a MOLM-13 xenograft model. Taken together, 13v may represent a starting point for the development of improved FLT3-ITD inhibitors.

Keywords

AML; FLT3-ITD; Proliferation inhibition.

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